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== '''Membrane fusion mechanism''' == | == '''Membrane fusion mechanism''' == | ||
[[Image:Membrane_fusion.jpg|thumbnail||800 px|| | |||
[[Image:Membrane_fusion.jpg|thumbnail||800 px||center| '''Membrane fusion mechanism.''']] | |||
Membrane Fusion requires the '''assembly of the core complex'''. '''Free t-SNAREs''' that are organized in '''clusters''' first assemble into acceptor complexes thanks to '''SM''' (Sec1/Munc18-related) '''proteins'''. Acceptor complexes can then interact with the '''v-SNAREs''' through the N-terminal domain of the SNARE motif. This enables the formation of '''four-helical trans-complexes''', in which only the N-terminal portions of the SNARE motifs are bound. This binding evolves from a '''loose''' to a '''tight state''', thus leading to the formation of a '''fusion pore'''. During the fusion, the conformation relaxes to a '''cis-configuration'''. Cis-complexes dissociate thanks to '''proteins''' and '''cofactors (SNAPs)'''. T- and v-SNAREs can be separated and recycled.<ref> PMID: 16912714 </ref> | Membrane Fusion requires the '''assembly of the core complex'''. '''Free t-SNAREs''' that are organized in '''clusters''' first assemble into acceptor complexes thanks to '''SM''' (Sec1/Munc18-related) '''proteins'''. Acceptor complexes can then interact with the '''v-SNAREs''' through the N-terminal domain of the SNARE motif. This enables the formation of '''four-helical trans-complexes''', in which only the N-terminal portions of the SNARE motifs are bound. This binding evolves from a '''loose''' to a '''tight state''', thus leading to the formation of a '''fusion pore'''. During the fusion, the conformation relaxes to a '''cis-configuration'''. Cis-complexes dissociate thanks to '''proteins''' and '''cofactors (SNAPs)'''. T- and v-SNAREs can be separated and recycled.<ref> PMID: 16912714 </ref> | ||
== '''Structure''' == | |||
=== ''SNARE domain'' === | === ''SNARE domain'' === | ||
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=== '' “0”-layers'' === | === '' “0”-layers'' === | ||
[[Image:Layers.png|thumbnail|| | |||
[[Image:Layers.png|thumbnail||1100 px||left| '''Topology of the 16 layers of the SNARE complex.''']] | |||
The centre of the four-helix bundle is constituted of '''16 layers'''. These layers are composed of '''hydrophobic side chains''', which are perpendicular to the axis of the four-helix bundle, except for the central '''“0”-layer'''. This last one consists of '''three glutamine (Q)''' and '''one arginine (R)''' highly conserved residues. Those highly conserved residues have led to a new classification of SNAREs into '''Q- and R-SNAREs'''. <ref> PMID: 9861047 </ref> Almost all membrane fusion reactions require one R-SNARE and three Q-SNAREs:Qa, Qb and Qc.<ref> PMID: 11237004 </ref><ref> PMID: 11001046 </ref> In many cases, the R-SNARE is in the vesicle, and the three Q-SNAREs are in the target membrane. For the early endosomal SNARE complex, syntaxin 13, vti1a, syntaxin 6, and VAMP4 were respectively classified as Qa-, Qb-, Qc- and R-SNAREs. | The centre of the four-helix bundle is constituted of '''16 layers'''. These layers are composed of '''hydrophobic side chains''', which are perpendicular to the axis of the four-helix bundle, except for the central '''“0”-layer'''. This last one consists of '''three glutamine (Q)''' and '''one arginine (R)''' highly conserved residues. Those highly conserved residues have led to a new classification of SNAREs into '''Q- and R-SNAREs'''. <ref> PMID: 9861047 </ref> Almost all membrane fusion reactions require one R-SNARE and three Q-SNAREs:Qa, Qb and Qc.<ref> PMID: 11237004 </ref><ref> PMID: 11001046 </ref> In many cases, the R-SNARE is in the vesicle, and the three Q-SNAREs are in the target membrane. For the early endosomal SNARE complex, syntaxin 13, vti1a, syntaxin 6, and VAMP4 were respectively classified as Qa-, Qb-, Qc- and R-SNAREs. | ||
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== '''Regulation''' == | |||
In addition to SNARE motifs and membrane anchors, SNARE proteins have '''autonomously folding N-terminal domains'''. These autonomously folded domains are able to '''regulate SNARE assembly'''. For example, synthaxin 7 has a '''three-helix-bundle domain''', which with the profiling-like domain Ykt6p of yeast can lightly '''inhibit the SNARE assembly'''.<ref> PMID: 11474112 </ref> Sso1p is the yeast ortholog of syntax in. Ssop has also '''three-helix-bundle domain''' that can bind to the SNARE motif. This binding generates a closed conformation that strongly '''inhibits the entry of Sso1p''' into SNARE complexes.<ref> PMID: 10048921 </ref><ref> PMID: 11017200 </ref><ref> PMID: 11777922 </ref><ref> PMID: 9731774 </ref> The main role of these autonomously folded domains is still under research. However, one of the known functions is the '''recruitment''' of other trafficking proteins thanks to the open/closed equilibrium of some SNAREs. | In addition to SNARE motifs and membrane anchors, SNARE proteins have '''autonomously folding N-terminal domains'''. These autonomously folded domains are able to '''regulate SNARE assembly'''. For example, synthaxin 7 has a '''three-helix-bundle domain''', which with the profiling-like domain Ykt6p of yeast can lightly '''inhibit the SNARE assembly'''.<ref> PMID: 11474112 </ref> Sso1p is the yeast ortholog of syntax in. Ssop has also '''three-helix-bundle domain''' that can bind to the SNARE motif. This binding generates a closed conformation that strongly '''inhibits the entry of Sso1p''' into SNARE complexes.<ref> PMID: 10048921 </ref><ref> PMID: 11017200 </ref><ref> PMID: 11777922 </ref><ref> PMID: 9731774 </ref> The main role of these autonomously folded domains is still under research. However, one of the known functions is the '''recruitment''' of other trafficking proteins thanks to the open/closed equilibrium of some SNAREs. | ||
== ''' SNAREs and pulmonary hypertension ''' == | == ''' SNAREs and pulmonary hypertension ''' == | ||
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== '''References''' == | == '''References''' == | ||
<references/> | |||
== '''Proteopedia page contributors and editors''' == | == '''Proteopedia page contributors and editors''' == | ||
Florence HERMAL and Camille ROESCH | Florence HERMAL and Camille ROESCH | ||